EP3323010A2 - Procédé relatif à la microscopie à contraste de phase, unité optique et microscope à contraste de phase - Google Patents

Procédé relatif à la microscopie à contraste de phase, unité optique et microscope à contraste de phase

Info

Publication number
EP3323010A2
EP3323010A2 EP16747864.3A EP16747864A EP3323010A2 EP 3323010 A2 EP3323010 A2 EP 3323010A2 EP 16747864 A EP16747864 A EP 16747864A EP 3323010 A2 EP3323010 A2 EP 3323010A2
Authority
EP
European Patent Office
Prior art keywords
phase
optical
illumination beam
deflection element
sample
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP16747864.3A
Other languages
German (de)
English (en)
Other versions
EP3323010B1 (fr
Inventor
Friedrich Schenk
Benedict Diederich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Original Assignee
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV filed Critical Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Publication of EP3323010A2 publication Critical patent/EP3323010A2/fr
Application granted granted Critical
Publication of EP3323010B1 publication Critical patent/EP3323010B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/06—Means for illuminating specimens
    • G02B21/08—Condensers
    • G02B21/14—Condensers affording illumination for phase-contrast observation
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/36—Microscopes arranged for photographic purposes or projection purposes or digital imaging or video purposes including associated control and data processing arrangements
    • G02B21/361—Optical details, e.g. image relay to the camera or image sensor
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/36—Microscopes arranged for photographic purposes or projection purposes or digital imaging or video purposes including associated control and data processing arrangements
    • G02B21/365—Control or image processing arrangements for digital or video microscopes

Definitions

  • the invention relates to a method for phase contrast microscopy according to the
  • the preamble of claim 1 an optical unit according to the preamble of claim 4 and a phase contrast microscope according to the preamble of claim 7.
  • Phase-contrast microscopy is mainly performed in transmitted light and is used on transparent objects such as living cells. Without particular measures to increase the contrast between radiation diffracted from a sample of undiffracted direct radiation and from the sample, the visibility of the sample is generally unsatisfactory. Staining to increase the contrast has an undesirable effect on the sample, especially in living cells.
  • Lens focal plane arranged and generally present in the form of a phase ring phase shift element, which comprises a phase-shifting delay element and a gray filter, phase-shifted and attenuated.
  • the sample radiation also undergoes a phase shift as it passes through the sample.
  • Direct radiation and sample radiation given resulting phase shift is converted into a change in amplitude, whereby in the intermediate image of the sample, the desired increase in contrast is achieved. It is important for the phase contrast that the image of the aperture of the phase stop is completely covered by the phase shift element in the rear focal plane of the lens, that is none Direct radiation passes the phase shift element and disturbs the intermediate image.
  • sample to be examined is arranged in liquid, referred to below as object liquid, in an open sample container, it forms
  • microtiter plates which consist of a plurality of mutually insulated, usually round, cup-shaped sample containers, so-called wells, in which the cells to be examined can be cultured surrounded by a nutrient medium.
  • microtiter plates which consist of a plurality of mutually insulated, usually round, cup-shaped sample containers, so-called wells, in which the cells to be examined can be cultured surrounded by a nutrient medium.
  • Microtiter plates have between 6 and 1536 individual wells on a base area of 128 x 85 mm. The result is a concavely curved object fluid meniscus within each well, the disturbing influence of which increases with decreasing diameter of the well. The stronger the meniscus is formed, that is to say in particular towards the edge of the well, the greater is the proportion of the direct radiation which occurs on the
  • Phase ring is guided over, so that the microscope is increasingly working in the bright field, whereby the contrast decreases significantly when imaging the cells.
  • overexposure in the resulting microscope image may result.
  • EP 1 859 866 A1 discloses a microtiter plate with a hydrophobic
  • a liquid crystal display (LCD) is used as a phase stop with LCD
  • Phase diaphragm changed to achieve the best possible coverage of the direct radiation with the phase ring.
  • the flexible deformation of the bezel by the LCD alone should not be enough to remedy the negative effects of
  • the LCD can only effect adjustments of the phase aperture shape within the plane perpendicular to the irradiation direction, which as a sole measure only results in a slight correction of the
  • An optical unit according to the preamble of claim 4 is known from US 3 514 192 A.
  • the liquid-filled prism is provided with transparent boundary walls whose angles are mutually variable, so that the refraction generated by the prism is controllable. It is known that the liquid-filled adaptive prism for compensating for image motion or for minimizing
  • the object is achieved by the characterizing features of claim 1. Accordingly, in order to compensate for a change in the main radiation direction of the illumination beam given due to optical refraction on the object liquid, the illumination beam is deflected before entry into the object fluid by means of an optical deflection element which can be changed in position and / or shape.
  • Sample container is parallel to its given before deflection by the deflection element original main radiation direction. It only comes to a lateral offset in the main radiation direction, but by a corresponding opposite lateral displacement of the illumination beam in front of it
  • Entering the deflection element can be corrected.
  • the latter is e.g. by a corresponding displacement of the source of the illumination beam, e.g. a phase stop.
  • At least partially compensated illumination beam and an overlap of direct radiation can be achieved with the phase shift element.
  • Changeability of the adaptation element in shape and / or position makes it possible to choose the deflection of the illumination beam as a function of the angle of the object liquid to the optical axis of the microscope.
  • the main radiation direction of the illumination beam in the context of this invention is its central axis extending in the beam direction, in the case of a symmetrical illumination beam, as may be the case in particular with an annular phase diaphragm, its axis of symmetry.
  • the inventive method can also be carried out so that a
  • Impact on the deflection element is changed by means of at least one variable optical matching element.
  • variable optical matching element which is preferably arranged in the radiation direction in front of the deflection element.
  • phase stop can, for example - as in the above represented prior art according to US 2012/0257040 A1 known - be realized by means of an LCD.
  • the contrast of the image of the sample to be microscoped is maximum.
  • the production of the illumination beam without phase diaphragm but by means of a suitable radiation source, for example an LED array.
  • the matching element may in this case be the LED array, wherein for different forms of the
  • the inventive method can also be carried out so that in
  • Beam path in front of the sample container generates an optical pattern, detects a generated in the region of the sample container optical distortion of the pattern and the degree of pattern distortion for automatically controlling the position and / or shape of the optical deflection element and / or for controlling the optical
  • Adjustment element is used.
  • the generation of the optical pattern e.g. with a regular grid structure, can be done by a separate unit or also by the LCD.
  • a fully automatic optimization of the contrast of the microscope image can be established by controlling, in particular, the parameters for the deflection element and / or the adaptation element.
  • An object of the invention is achieved in that the entry surface is predetermined by a surface of the viscous mass formed in a gravitational field. This is a very effective and simple but effective variant of an adaptive
  • the deflection element serves to deflect the main radiation direction of the illumination beam when needed.
  • the optical unit can also be used outside of a phase-contrast microscope in order to be able to use the variability of the adaptive deflection element for the controlled manipulation of a radiation passing through the deflection element.
  • the viscous mass has a higher optical density than the atmosphere surrounding the deflection element, in particular air, and may for example consist of a liquid, for example water, or a gel.
  • the viscous mass can also correspond in material and / or optical property to the optical density of the object liquid in the sample container.
  • the baffle may comprise an open container with the viscous mass so that the entrance surface is directly formed by the surface of the viscous masses.
  • the optical unit may also be designed so that the entrance surface is formed by a directly or indirectly on the surface of the viscous mass floating or resting, rigid and transparent cover member.
  • Cover member preferably has a raised edge to prevent spilling over of the viscous mass onto the top surface of the cover member. Through the surface of the viscous mass, the position of the cover element in space and thus also the position of the entrance surface is predetermined.
  • the optical unit with means for pivoting the
  • Be deflecting element provided at least one pivot axis.
  • Gravity field remains the surface entering the surface of the viscous mass, preferably a liquid, even with a pivoting movement about a vertical axis of gravity pivot axis aligned horizontally, while given by a given in a transparent bottom wall of a carrier for the viscous mass exit surface during the pivoting movement of their angle to
  • a deflection element which is constant in its shape and whose surfaces have spatially different angles to one another on an entrance side for the illumination beam on the one hand and on an exit side for the illumination beam.
  • the entrance side could be just shaped and the
  • Exit surface have a single or multiple curved course.
  • a deflection element could be placed in such a way that the illumination beam enters the entrance side perpendicularly and exits at the exit side at a point at which the exit surface does not run parallel to the entry surface, so that the
  • Lighting bundle is broken accordingly. If such an optical element is now displaced laterally, the angular relationship between the entrance surface and the exit surface changes for the illumination bundle, so that the deflection of the illumination element also changes
  • shape-constant deflection element means for carrying out pivotal movements by at least one parallel to the entrance surface
  • Pivot axis or rotations e.g. one to the direction of the entering
  • the deflection element can be designed so that any one of the following properties:
  • Irradiation directions can be provided, in particular in the horizontal direction, so that there is no more dependence on the orientation of the gravitational field.
  • a vessel forming the deflecting element can also be open at the top or else from a flexible skin, e.g. a diaphragm, so that the viscous mass can follow the movement of the boundary wall or several boundary walls.
  • seals or the boundary walls interconnecting flexible, e.g. foil-like, wall elements e.g. be provided of a rubber, which allow the movement of adjacent boundary walls to each other.
  • the means for controlled movement of the at least one boundary wall may be actuators equipped with motors or hydraulically or pneumatically driven.
  • the optical unit according to the invention can be equipped with means for translational and / or rotational movement of the deflection element.
  • the overlap of direct radiation and phase shift element is optically controlled, for which purpose a Bertrand lens unit with at least one deformable in its focal position formable lens is preferably used.
  • the focal position can be adjusted with means for controlling the at least one moldable lens. In this way, it is possible to leave the Bertrand lens unit permanently in the microscope and to switch between an operating state for microscopy, i. for observing the sample, and an operating state for controlling the overlap of direct radiation with the phase shifting element, i. to check the correct mapping of the phase aperture on the
  • Phase shift element to switch. Swiveling in a Bertrand lens or the use of a semitransparent mirror is therefore no longer necessary.
  • Fig. 1 a phase contrast microscope
  • FIG. 2a shows a detail of the phase contrast microscope without deflection of the illumination beam through a deflection element
  • Fig. 2b the position of the phase ring in the situation shown in Fig. 2a;
  • FIG. 3a the detail of FIG. 2a with deflection of
  • Fig. 3b the position of the phase ring in the situation shown in Fig. 3a;
  • FIG. 5 shows the detail according to FIG. 4 in a second operating state of FIG
  • Fig. 6 an alternative embodiment of a deflection element.
  • Fig. 1 shows schematically a phase contrast microscope, wherein the individual
  • Illuminating beam 3 not shown but only schematically an area indicated within which the illumination beam 3 extends with a main radiation direction 28 shown here by a solid line.
  • the illumination beam 3 After exiting the phase diaphragm 2, the illumination beam 3 hits a
  • Condenser 4 which focuses the illumination beam 3 on a sample not separately shown here, which is located within a sample container 5, which has an object liquid 6.
  • the sample container 5 may be, for example, the well of a microtiter plate. However, the sample container 5 may also be a single container or other container combination. In Figs. 1, 2a and 3a of the
  • Sample container 5 is supported by an object holder 7 whose position is preferably variable by means of a controller 22. In a corresponding manner, a microtiter plate or another object with at least one sample container 5 would also be carried by the object holder 7.
  • an adaptive deflection element 8 in which a deflection element liquid 9 is located.
  • the deflecting element liquid 9 is transparent to the radiation of the illumination beam 3, in the case of FIG. 1 forms an entrance surface 29 for the illumination beam 3 and can be, for example, water.
  • the deflecting element 8 liquids are used which are of the optical behavior that of the object liquid 6, e.g. of a nutrient medium.
  • the deflecting element liquid 9 may be provided in part with a cover 10, which is also transparent to the radiation used by the illuminating beam 3 and thus forms its entrance surface 29 to the deflecting element 8.
  • the cover 10, for example, by a
  • the illumination beam 3 passes through an objective 1 1, which has a phase ring 12.
  • the phase ring 12 comprises a phase-shifting
  • Delay element and a gray filter both not shown in detail here, whereby the incident portion of the illumination beam 3 is attenuated and shifted in phase.
  • the radiation passes through an optional tube lens 13, depending on the type of phase contrast microscope, as well as a
  • Bertrandlinsen unit 14 before it hits the image sensor 15 of a camera 16.
  • the sample should be analyzed by means of a portion of the sample which is not bent by the sample
  • Illuminating beam 3 the annular opening of the phase diaphragm 2 are completely mapped to the phase ring 12.
  • a portion of the illumination beam 3 diffracted by the sample passes by the phase ring 12 and interferes with the direct radiation to the high-contrast microscope image of the sample.
  • the image is viewed with an eyepiece or - as shown here as an advantageous variant - an image sensor 15 of a camera 16.
  • FIG. 2 a shows a situation in which the illumination beam 3 strikes the center of the sample container 5. There is a meniscus of the surface of the object liquid 6 is not or only weakly formed. The illumination beam 3 thus falls on the objective 1 1 and the phase ring 12 (see FIG. 1) without experiencing a substantial refraction through the sample container 6 and its object liquid 6. The phase ring 12 and the phase diaphragm 2 are aligned with each other for this undisturbed by the sample container 5 radiation path, so that the direct radiation completely falls on the phase ring 12.
  • Fig. 3a shows the situation in which a sample area is to be examined, which is positioned closer to the edge of the sample container 5, where due to the
  • the deflection element 8 is inclined, so that serving for the radiation as the exit surface 23 lower boundary surface of the deflection element 8 is no longer perpendicular to the main radiation direction 28 and at the exit surface 23, a refraction of the illumination beam 3 with a change of
  • Main radiation direction 28 takes place.
  • the degree of inclination of the deflection element 8 and thus the deflection of the main radiation direction is to be chosen so that the
  • Sample container 5 is parallel to the optical axis of the adjoining in the beam direction of the sample container 5 part of the microscope. If the optical density of the deflection element 8 is equal to the optical density of the object liquid 6, the inclination is preferably selected so that the exit surface 23 is aligned parallel to the tangent to the surface curvature of the object liquid 6.
  • Bearing element 8 mounted on a pivotable about two pivot axes and not shown here holder.
  • the two pivot axes are perpendicular to the main radiation direction 28 of the illumination beam 3.
  • the baffle 8 changes shape because the surface of the baffle liquid 9 is still oriented perpendicular to the direction of gravity.
  • the deflection element 8 thus forms by means of the means for pivoting, not shown in Fig. 2a and 3a, an adaptive prism.
  • the illumination beam 3 undergoes a refraction, ie a deflection of the main radiation direction 28, at a deflecting element 8 pivoted by an angle ⁇ through the exit surface 23, and is refracted at the surface of the object liquid 6.
  • the illumination beam 3 undergoes a further refraction, so that the main radiation direction 28 again parallel to the prior to hitting the baffle 8 given original
  • Main radiation direction 28 is running. It only has a lateral shift
  • phase diaphragm 2 which is shown only schematically in FIGS. 1, 2a and 3a, can thus be realized by a conventional rigid phase diaphragm body, which is displaceable only within a plane parallel to its center plane.
  • phase diaphragm 2 by a
  • LCD Liquid crystal display
  • the LCD could function as electronically variable phase stop 2, advantageously not only a shift of the phase aperture 30 as a whole is possible, but also a change in the shape of the phase aperture 30 can be performed.
  • phase-aperture opening 30 may become necessary if, for example due to the particular strength of the curvature of the meniscus of the object liquid 6, a distorted imaging of the phase-aperture opening 30 occurs.
  • the Bertrandlinsen unit 14 shown in Fig. 1 will be explained in more detail below with reference to FIGS. 4 and 5.
  • the variant of the Bertrand lens unit 14 shown here is not mandatory. It is alternatively possible in the inventive
  • Phase contrast microscope to turn a known Bertrand lens in the beam path of the phase contrast microscope or with a semi-transparent mirror to provide for the connection of an external Bertrand lens. It is known from the prior art that a Bertrand lens is used to control the imaging of the opening of the phase stop 2 on the phase ring 12.
  • Fig. 1 and a fragmentary Fig. 4 and 5 a phase contrast microscope with Bertrand lens unit 14, which may be permanently in the beam path of the phase contrast microscope.
  • the Bertrand lens unit 14 is switchable and comprises a eg electronically deformable lens 17. This makes it possible to produce an optical system which is capable of providing both an image of the back focal plane and the phase ring 12 located there as needed, as well as focusing the system on the sample.
  • the focus variable lens 17 is switched from a small to a large focal length, so that the coordinated
  • FIG. 5 shows the situation when the "Bertrand lens unit 14" is switched off. In this case, the sample is sharply imaged on the image sensor 15
  • the phase-contrast microscope according to the invention makes it possible to automatically adjust the position or the swivel angle of the deflection element 8 and / or the position and optionally the shape of the phase diaphragm 2.
  • the following procedure can be adopted:
  • Deflection element (in FIG. 1, only ⁇ is shown) is first equated to the angle values ⁇ 'and ⁇ ' of the tangent of the object liquid surface above the center of the sample point to be observed. For very different optical densities, adjusted angle values can also be used.
  • the phase diaphragm 2 is displaced by an appropriate to the expected parallel displacement of the main beam direction 28 measure in their direction perpendicular to the beam direction of the source light beam 1 x- / y-plane.
  • the Bertrand lens unit 14 for imaging the phase ring 12 is switched to the image sensor 15. This is done by means of a controller 19 shown schematically for the Bertrandlinsen unit 14 in FIG. 1.
  • the image of the phase ring generated on the image sensor 15 of the camera 16 is automatically evaluated and checked with respect to the overlap of the image of the opening of the phase diaphragm 2 with the phase ring 12 ,
  • the overlapping of the images can be assessed not only on the basis of the intermediate image of the phase ring 12, but alternatively or additionally directly on the basis of the restored image contrast of the object image, which can be switched back by switching the Bertrand lens unit 14.
  • the surface curvature may be directly out of
  • Intermediate image plane can be determined by a instead of the phase aperture certain pattern, for example a grid structure, on the rear
  • the pattern which is not shown in the figures, can advantageously be generated by means of an electronically controllable adaptive element, for example by means of the same LCD, which can also function as a phase stop 2.
  • distortions of the discontinued pattern can be determined by algorithms, the shape of the pattern distortion generated by the curvature of the surface of the object liquid 6. From these
  • the parameters for adapting the phase diaphragm 2 and the deflection element 8 can be calculated.
  • Fig. 6 shows schematically an alternative deflection element 24 made of a solid material, e.g. Glass, devisschettik one only partially shown
  • a solid material e.g. Glass
  • Sample container 5 An upper entrance surface 25 is planar, while an opposite exit surface 26 is convexly curved. Several alternative main radiation directions 27a to 27e of the illumination beam 3 are symbolized. While the illumination beam 3 with the main radiation direction 27a passes unbroken through the deflection element 24, the illumination beam 3 undergoes a stronger refraction in the case of the main radiation directions 27b to 27e.
  • the deflection of the main radiation direction 27d effected by the deflection element 24 leads to the desired compensation of the refraction generated by the object liquid 6. If another point of the sample, not shown here, is to be examined in the sample container 5, which has a different curvature of the surface of the object liquid 6, it may be necessary to displace the deflection element 24 relative to the sample container 5 in order to deflect the illumination bundle 3 to the other Curvature of the surface of the object liquid 6 adapt.
  • the relative movement between the deflection element 24 and the sample container 5 is effected by a translation of the deflection element 24 in the phase contrast microscope.

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  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Multimedia (AREA)
  • Computer Vision & Pattern Recognition (AREA)
  • Microscoopes, Condenser (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

Procédé relatif à la microscopie à contraste de phase sur un échantillon placé dans un récipient pour échantillon (5) contenant un liquide objet (6), selon lequel une partie d'un faisceau d'éclairage (3, 27), non diffractée par l'échantillon et servant de rayonnement direct, est envoyée sur un élément de décalage de phase (12), caractérisé en ce que pour compenser la modification d'une direction principale de rayonnement (28) du faisceau d'éclairage (3, 27), provoquée par la réfraction optique au niveau du liquide objet (6), le faisceau d'éclairage (3, 27) est dévié, avant son entrée dans le liquide objet (6), au moyen d'un élément de déviation optique (8, 24) dont la forme et/ou la position peut être modifiée. Une unité optique, qui comporte un élément de déviation optique (8) présentant une surface d'entrée (25, 29) et une surface de sortie (23, 26), ainsi que des moyens pour modifier de manière commandée l'angle entre la surface d'entrée (25, 29) et la surface de sortie (23, 26), une substance visqueuse (9) étant placée entre la surface d'entrée (25, 29) et la surface de sortie (23, 26), est caractérisée en ce que la surface d'entrée (25, 29) est constituée par une surface de la substance visqueuse (9), formée dans un champ de gravitation. La présente invention concerne enfin un microscope à contraste de phase permettant la mise en oeuvre dudit procédé.
EP16747864.3A 2015-07-14 2016-07-13 Procédé relatif à la microscopie à contraste de phase, unité optique et microscope à contraste de phase Active EP3323010B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102015111426.7A DE102015111426B3 (de) 2015-07-14 2015-07-14 Verfahren zur Phasenkontrastmikroskopie sowie Phasenkontrastmikroskop
PCT/EP2016/066671 WO2017009383A2 (fr) 2015-07-14 2016-07-13 Procédé relatif à la microscopie à contraste de phase, unité optique et microscope à contraste de phase

Publications (2)

Publication Number Publication Date
EP3323010A2 true EP3323010A2 (fr) 2018-05-23
EP3323010B1 EP3323010B1 (fr) 2019-01-09

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US (1) US10921572B2 (fr)
EP (1) EP3323010B1 (fr)
JP (1) JP6782761B2 (fr)
DE (1) DE102015111426B3 (fr)
WO (1) WO2017009383A2 (fr)

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JP6411294B2 (ja) * 2015-06-30 2018-10-24 富士フイルム株式会社 位相差顕微鏡および撮像方法

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US20180129030A1 (en) 2018-05-10
WO2017009383A2 (fr) 2017-01-19
JP2018522282A (ja) 2018-08-09
EP3323010B1 (fr) 2019-01-09
DE102015111426B3 (de) 2016-10-20
JP6782761B2 (ja) 2020-11-11
US10921572B2 (en) 2021-02-16

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